U.S. patent number 9,198,868 [Application Number 13/881,664] was granted by the patent office on 2015-12-01 for bulk enteric capsule shells.
This patent grant is currently assigned to Capsugel Belgium NV. The grantee listed for this patent is Hassan Benameur, Dominique Nicolas Cade, Sophie Schreiber. Invention is credited to Hassan Benameur, Dominique Nicolas Cade, Sophie Schreiber.
United States Patent |
9,198,868 |
Benameur , et al. |
December 1, 2015 |
**Please see images for:
( Certificate of Correction ) ** |
Bulk enteric capsule shells
Abstract
The present disclosure relates to aqueous compositions for use
in the manufacture of capsule shells endowed with bulk enteric
properties. The present disclosure also relates, in part, to
aqueous dispersions suitable for the implementation of said
manufacturing process, and to enteric capsule shells and hard
capsules obtained therewith.
Inventors: |
Benameur; Hassan (Eaubonne,
FR), Cade; Dominique Nicolas (Colmar, FR),
Schreiber; Sophie (Colmar, FR) |
Applicant: |
Name |
City |
State |
Country |
Type |
Benameur; Hassan
Cade; Dominique Nicolas
Schreiber; Sophie |
Eaubonne
Colmar
Colmar |
N/A
N/A
N/A |
FR
FR
FR |
|
|
Assignee: |
Capsugel Belgium NV (Bornem,
BE)
|
Family
ID: |
45491631 |
Appl.
No.: |
13/881,664 |
Filed: |
October 24, 2011 |
PCT
Filed: |
October 24, 2011 |
PCT No.: |
PCT/IB2011/002894 |
371(c)(1),(2),(4) Date: |
July 15, 2013 |
PCT
Pub. No.: |
WO2012/056321 |
PCT
Pub. Date: |
May 03, 2012 |
Prior Publication Data
|
|
|
|
Document
Identifier |
Publication Date |
|
US 20130287840 A1 |
Oct 31, 2013 |
|
Related U.S. Patent Documents
|
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
Issue Date |
|
|
61406701 |
Oct 26, 2010 |
|
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K
31/167 (20130101); C09B 67/0097 (20130101); A61K
9/4816 (20130101); A61K 47/38 (20130101); B01J
13/04 (20130101) |
Current International
Class: |
A61K
9/48 (20060101); A61K 47/38 (20060101); B01J
13/04 (20060101); C09B 67/02 (20060101); A61K
31/167 (20060101) |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
|
|
|
|
|
|
|
1258500 |
|
Jul 2000 |
|
CN |
|
0223685 |
|
May 1987 |
|
EP |
|
0401832 |
|
Dec 1990 |
|
EP |
|
1447082 |
|
Aug 2004 |
|
EP |
|
1310697 |
|
Mar 1973 |
|
GB |
|
S57-142251 |
|
Sep 1982 |
|
JP |
|
2006-505542 |
|
Feb 2006 |
|
JP |
|
WO 00/18377 |
|
Apr 2000 |
|
WO |
|
WO 2004/030658 |
|
Apr 2004 |
|
WO |
|
WO 2007/027560 |
|
Mar 2007 |
|
WO |
|
WO 2008/050209 |
|
May 2008 |
|
WO |
|
WO 2008/119943 |
|
Oct 2008 |
|
WO |
|
WO 2009/050646 |
|
Apr 2009 |
|
WO |
|
WO 2009/138920 |
|
Nov 2009 |
|
WO |
|
Other References
Felton et al., Pharm Sci 2002, 4, Abstract T3320. cited by
applicant .
Han et al., Journal of Pharmaceutical Sciences, vol. 98, No. 8,
Aug. 2009. cited by applicant .
Huyghebaert et al., Eur J Pharm Sci 2004, 21, 617-623. cited by
applicant .
International Search Report mailed Jun. 4, 2012 for International
Application No. PCT/IB2011/002894. cited by applicant .
Kirilmaz L., S.T.P. Pharma Sciences, Nov. 10, 1993 3/5, 374-378.
cited by applicant .
Thoma et al., Capsugel Technical Bulletin 1986, 1-16. cited by
applicant .
Felton, L.A. et al., "Enteric Film Coating of Soft Gelatin
Capsules", Drug Development and Delivery, Sep. 2003, vol. 3, No. 6,
posted on Mar. 28, 2008. cited by applicant .
English-language translation of Search Report and Office Action
issued in corresponding Chinese Patent Application No.
201180061971.1, Nov. 4, 2014 (13 pages). cited by applicant .
English-language translation of Notice of Reasons for Rejection
issued in corresponding Japanese Patent Application No.
2013-535531, Jul. 7, 2015 (8 pages). cited by applicant.
|
Primary Examiner: Haghighatian; Mina
Assistant Examiner: Karpinski; Luke
Attorney, Agent or Firm: Klarquist Sparkman, LLP
Parent Case Text
This application is a national stage entry under 35 U.S.C.
.sctn.371 of International Application No. PCT/IB2011/002894, filed
Oct. 24, 2011 which claims priority of U.S. provisional application
No. 61/406,701, filed Oct. 26, 2010, all of which are incorporated
herein by reference in their entirety.
This application claims priority to U.S. Provisional Application
No. 61/406,701, filed on Oct. 26, 2010, the disclosure of which is
incorporated herein by reference in its entirety.
Claims
What is claimed is:
1. An aqueous composition for the manufacture of enteric hard
capsule shells, comprising: (a) an aqueous dispersion of
non-salified cellulose acetate phthalate (CAP), said CAP being
present in an amount ranging from about 10% to about 40% by weight
of the total weight of said aqueous composition; (b) at least one
processing aid present in an amount ranging from about 4% to about
20% by weight of the total weight of said aqueous composition,
wherein said at least one processing aid is selected from
polyoxyethylene-polyoxypropylene-polyoxyethylene tri-block polymers
or mixtures thereof, having an average molecular weight ranging
from about 1000 to about 20000 and a polyoxyethylene ratio ranging
from about 10% to about 85%; and (c) water.
2. The composition according to claim 1, wherein the total amount
of the CAP and the at least one processing aid range from about
14.9% to about 50% combined, by weight of the total weight of the
composition.
3. The composition according to claim 1, wherein the CAP is in the
form of finely divided solid particles having an average diameter
ranging from about 0.1 to about 10 microns.
4. The composition according to claim 1, wherein the at least one
processing aid is selected from poloxamers or mixtures thereof.
5. The composition according to claim 1, further comprising at
least one pharmaceutically acceptable or food acceptable colouring
agent.
6. The composition according to claim 1, further comprising at
least one film forming aid.
7. The composition according to claim 6, wherein the at least one
film forming aid is selected from thickening agents, structuring
agents, surfactants, and plasticizers.
8. The composition according to claim 6, wherein the at least one
film forming aid is selected from hypromellose; alkyl cellulose and
other cellulosic derivatives; polyvinyl acetate derivatives (PV
AP); polysaccharides; glyceryl esters; glycol esters; sorbitan
monoesters; sorbitan polyoxyethylene esters; polyoxyethylene (POE)
ethers; glycerol; polyethylene glycols; polyols; fatty acid esters;
glycerol polyethylene, glycol ricinoleate; macrogolglycerides; SLS;
triethyl citrate (TEC); Triacetine; alkyl phthalate; and mixtures
thereof.
9. The composition according to claim 7, wherein the at least one
film forming aid is selected from HPMC, HPC, EC, MC, CMEC, HPMCAS,
and HPMCP.
10. A dip-moulding process for the manufacture of bulk enteric hard
capsule shells, comprising: i) providing an aqueous composition
comprising (a) an aqueous dispersion of a non-salified cellulose
acetate phthalate (CAP), said CAP being present in an amount
ranging from about 10% to about 40% by weight of the total weight
of said aqueous composition; (b) at least one processing aid
present in an amount ranging from about 4% to about 20% by weight
of the total weight of said aqueous composition, wherein said at
least one processing aid is a
polyoxyethylene-polyoxypropylene-polyoxyethylene tri-block polymer
or a mixture of polyoxyethylene-polyoxypropylene-polyoxyethylene
tri-block polymers, and having an average molecular weight ranging
from about 1000 to about 20000 and a polyoxyethylene ratio ranging
from about 10% to about 85%; and (c) water; ii) adjusting said
aqueous composition to a temperature (TI) ranging from about
5.degree. C. to about 40.degree. C.; iii) pre-heating moulding pins
to a dipping temperature (T2) ranging from about 15.degree. C. to
about 70.degree. C. higher than said temperature T1; iv) dipping
the pre-heated moulding pins into said aqueous composition; v)
forming a film on said moulding pins by withdrawing said pins from
said aqueous composition; and vi) drying the film on said moulding
pins to form bulk enteric hard capsule shells.
11. The process according to claim 10, wherein T1 ranges from about
15.degree. C. to about 35.degree. C.
12. The process according to claim 10, wherein T2 ranges from about
25.degree. C. to about 50.degree. C. higher than said temperature
TI.
13. The process according to claim 10, wherein step iv) comprises a
single dipping of the pins.
14. The process according to claim 10, further comprising a step
vii) filling said hard capsule shells with at least one active
ingredient.
15. A bulk enteric hard capsule shell comprising: (A) non-salified
cellulose acetate phthalate (CAP), said CAP being present in an
amount ranging from about 40% to about 70% by weight of the total
weight of said capsule shell; (B) at least one processing aid
present in an amount ranging from about 15% to about 49% by weight
of the total weight of said capsule shell, wherein said at least
one processing aid is selected from
polyoxyethylene-polyoxypropylene-polyoxyethylene tri-block polymers
or mixtures thereof, and having an average molecular weight ranging
from about 1000 to about 20000 and a polyoxyethylene ratio ranging
from about 10% to about 80%; and (C) water, wherein the capsule
shell is produced by the process of claim 10.
16. The hard capsule shell according to claim 15, further
comprising at least one encapsulated active ingredient.
17. The hard capsule shell according to claim 16, wherein the
amount of water, as equilibrated with the relative humidity of the
outside air, ranges from about 2% to about 20% by weight of the
total weight of the capsule shell.
18. The hard capsule shell according to claim 17, wherein the at
least one active ingredient comprises a solid, semi-solid, or
liquid form.
19. The hard capsule shell according to claim 15, comprising a
disintegration release of less than about 10% of the total
encapsulated at least one active ingredient after a time of about 2
hours at a pH of about 1.2; and a dissolution release of less than
about 10% of the total encapsulated at least one active ingredient
after at time of about 2 hours at a pH of about 1.2.
20. The hard capsule shell according to claim 19, wherein the
dissolution release is about 80% of the total encapsulated at least
one active ingredient at a time of about 45 minutes at a pH of
about 6.8.
Description
The present disclosure relates to aqueous compositions for use in
the manufacture of capsule shells endowed with bulk enteric
properties. The present disclosure also relates, in part, to
aqueous dispersions suitable for the implementation of said
manufacturing process, and to enteric capsule shells and hard
capsules obtained therewith.
Capsules are well-known dosage forms that normally consist of a
shell filled with one or more specific substances. The shell itself
may be a soft or a hard stable shell. Hard capsule shells are
generally manufactured using dip moulding processes, which can be
distinguished into two alternative procedures. In the first
procedure, capsules are prepared by dipping stainless-steel mould
pins into a solution of polymer, optionally containing one or more
gelling agents (e.g. carrageenans) and co-gelling agents (e.g.
inorganic cations). The mould pins are subsequently removed,
inverted, and dried to form a film on the surface. The dried
capsule films are then removed from the moulds, cut to the desired
length, and then the caps and bodies are assembled, printed, and
packaged. See e.g., U.S. Pat. No. 5,264,223, U.S. Pat. No.
5,756,123, and U.S. Pat. No. 5,756,123.
In the second procedure, no gelling agents or co-gelling agents are
used and film-forming polymer solution gelifications on the
moulding pins are thermally induced by dipping pre-heated moulding
pins into the polymer solution. This second process is commonly
referred to as thermogellation or thermogelling dip moulding. See,
e.g., EP 0401832, U.S. Pat. No. 3,493,407, U.S. Pat. No. 4,001,211,
GB1310697, U.S. Pat. No. 3,617,588 and WO 2008/050209. In each of
the aforementioned processes, both utilize a solution of the
different ingredients that constitute the capsule shell wall.
Once the capsules are formed, different techniques have been used
to impart enteric properties to the hard or soft capsule shells.
One such technique involves treating the surface of the
pre-manufactured capsules (e.g. spraying or film-coating already
manufactured capsules) with one or more layers of a substance or
composition that is known to impart enteric properties. However,
this technique is time-consuming, complex, and consists of
expensive multiple step process. In addition, hard capsule shells
made by this process must typically be pre-filled and sealed, or
banded, before the surface is treated. As a result, it is not
possible to use this process to make or commercialize hard capsule
shells in a pre-locked status. Thus, the determination of the
adequate filling parameters is left with the end user.
In an attempt to overcome these drawbacks, another technique used
to impart enteric properties to hard or soft capsule shells
involves the direct use of enteric polymers (acid-insoluble
polymers) within the context of the hard shell manufacturing
process. Thus, in this technique, the impartation of the enteric
properties occurs during the manufacturing process as opposed to
treating capsules which have already been pre-formed. However, when
enteric polymers are used in large amounts, which are otherwise
theoretically necessary for commercialization of the hard capsule
shells manufacture, enteric polymers are poorly or completely water
insoluble. Thus, the use of the process on a commercial scale
raises a significant problem with respect to the effectiveness at
which one can use this process under conventional dip moulding
techniques. In addition, this method of coating works well on a
small scale for hydroxypropyl methylcellulose (HMPC) capsules, but
in the case of gelatin capsules, poor adhesion of the coat to the
smooth gelatin surface can result in brittleness of the capsule.
See, e.g., Huyghebaert et al., Eur J Pharm Sci 2004, 21, 617-623;
Felton et al., Pharm Sci 2002, 4, Abstract T3320, and Thoma et al.,
Capsugel Technical Bulletin 1986, 1-16.
Attempts to overcome the deficiencies discussed above range from
(i) using low, water-soluble amounts of acid-insoluble polymers in
combination with major amounts of conventional film forming
polymers; (ii) salifying the water-insoluble polymers to obtain
water-soluble derivatives; (iii) using solvent-based dipping
solutions instead of water-based ones; and (iv) using alternative
techniques, such as injection moulding, which do not require
polymer solubilization. See e.g., WO 2004/030658; WO2008/119943;
EP1447082; U.S. Pat. No. 4,138,013; U.S. Pat. No. 2,718,667; EP
223685A1; Han et al., Journal of Pharmaceutical Sciences, Vol. 98,
No. 8, August 2009; and Kirilmaz L., S.T.P. Pharma Sciences, Nov.
10, 1993, 3/5 (374-378).
Despite this progress, many of the techniques described above still
require the addition of enteric (acid insoluble polymer) polymers,
require salts or pH regulators, require multiple processing steps,
and/or need to be processed in non-aqueous media. Thus, there is a
need to develop a rapid, safe, and economic way to generate hard
capsule shells displaying enteric properties, while maintaining
optimal chemical and mechanical properties, and without the need
for conventional acid insoluble polymers and/or non-aqueous media,
or requiring additional processing steps, e.g., coating the enteric
polymer or double dipping.
Accordingly, one aspect of the present disclosure provides
water-based compositions comprising cellulose acetate phthalate
(CAP) that display appropriate solid content, viscosity at room
temperature, setting properties, and rheological behavior for use
in the manufacture of hard capsule shells.
In another aspect, the present disclosure relates to films and hard
capsule shells obtained from the aforementioned water-based
compositions, wherein the films and/or hard capsule shells display
bulk enteric properties and exhibit optimal chemical and mechanical
properties, e.g., disintegration profile, dissolution profile, film
thickness, tensile strength values.
In another aspect, the present disclosure provides films and hard
capsule shells displaying enteric properties, which are free of
non-aqueous media/solvents.
In another aspect, the present disclosure provides rapid, economic,
safe and easy to realize dip-moulding processes for the manufacture
of hard capsule shells displaying bulk enteric properties
(hereinafter also referred to as "enteric hard capsule shells"). In
yet another aspect, the present disclosure provides a rapid,
economic, safe and easy to realize "one step" dip-moulding process
for the manufacture of hard capsule shells, wherein the co-presence
of conventional film-forming non enteric polymers is no longer
necessary.
DEFINITIONS
As used in the present disclosure, the following words, phrases,
and symbols are generally intended to have the meanings as set
forth below, except to the extent that the context in which they
are used indicates otherwise.
As used herein, "optional" or "optionally" means that the
subsequently described even or circumstance may or may not occur,
and that the description includes instances where the event or
circumstance occurs and instances in which it does not.
As used herein, "w/w %" means by weight as a percentage of the
total weight.
The term "about" is intended to mean approximately, in the region
of, roughly, or around. When the term "about" is used in
conjunction with a numerical range, it modifies that range by
extending the boundaries above and below the numerical values set
forth. Unless otherwise indicated, it should be understood that the
numerical parameters set forth in the following specification and
attached claims are approximations. At the very least, and not as
an attempt to limit the application of the doctrine of equivalents
to the scope of the claims, numerical parameters should be read in
light of the number of reported significant digits and the
application of ordinary rounding techniques.
Unless otherwise indicated, "cellulose acetate phthalate" is also
referred to as CAP, and is commonly known in the field of polymers
with the following alternative nomenclature: CAS registry number
9004-38-0; chemical common synonyms, such as: acetyl phthalyl
cellulose, cellulose acetate hydrogen 1,2-benzenedicarboxylate,
cellulose acetate hydrogen phthalate, cellulose acetate
monophthalate, cellulose acetophthalate, and cellulose acetyl
phthalate; and non proprietary names, such as: cellacephate
(British Pharmacopeia), cellulose acetate phthalate (Japanese
Pharmacopeia), cellulosi acetas phthalas (PhEur), and cellacefate
(US Pharmacopeia).
Unless otherwise indicated, "non-salified CAP" means that CAP free
acid residues (e.g., the carboxylic acid residues of the phthalate
and acetate moieties present in the molecule) are not salified. For
example, salification with carbonates, bicarbonates, hydrogen
phosphates and hydroxides of elements of Groups I and II of the
periodic table, or nitrogen containing base compounds (e.g.,
ammonia or primary, secondary or tertiary organic amines or amine
derivatives), are excluded. The CAP may be non-salified in any one
of the manufacturing steps of the hard capsule shells and capsules
as described herein. Nonetheless, unwanted salification of
technically irrelevant amounts of CAP may be tolerated as the
result of the presence of salifying basic impurities in other
ingredients used in the manufacturing processes for the hard
capsule shells and capsules. Similarly, if purchased non-salified
CAP contains salified CAP as an impurity, this is tolerable. In
some instances, traces or impurities of salified CAP can be present
in the aqueous compositions, hard capsule shells or capsules of the
present disclosure. Traces or impurities of salified CAP can be,
for example, less than 1% by weight over the weight of the total
CAP present.
Unless otherwise indicated, the CAP is present in a dispersed state
in the aqueous compositions described herein. Thus, the aqueous
compositions comprise finely divided non-salified CAP solid
particles having average diameters ranging from about 0.1 to about
10 microns. CAP dispersions are commercially available and can be
either purchased (e.g. FMC Aquacoat.RTM. CPD30) or obtained by
re-dispersing a commercially available powdered non-salified CAP
(e.g. the FMC Aquateric.RTM. product or CAP available from Eastman
chemical) in water. It will be understood that other ingredients in
the aqueous compositions described herein, e.g., the processing
aids, may be present in the dissolved state, dispersed state, or
mixtures thereof depending on the solubility properties of the
other ingredients.
The term "solids" includes at least all non-aqueous ingredients
present in the aqueous compositions, capsule shells, and capsules
described herein. For example, "solids" include, but are not
limited to, ingredients a) (or A)) and b) (or B)), plus any
additional and optional ingredients. For example, solids include
CAP (for example CAP from Eastman), the processing aid, all
optional non-aqueous ingredients pre-formulated in commercially
available CAP products, e.g., FMC Aquateric or Aquacoat CPD
30.RTM.. Other solids are discussed below in connection with
optional ingredients of the aqueous compositions, capsule shells,
and capsules described herein.
Unless otherwise indicated, hard capsules described herein have the
same or similar shape of commercially available, conventional hard
capsules intended for oral administration to human or animal
subjects. The hard capsules described herein can be manufactured
using different processes, such as the dip moulding processes
discussed below as well as the use of conventional equipment. As is
described in detail below, pin moulds may be dipped into an
aqueous-based film forming composition and subsequently withdrawn.
The film formed on the moulding pins surface can then be dried,
stripped off the pins and cut to a desired length, thereby
obtaining the capsules caps and bodies. Normally, caps and bodies
have a side wall, an open end and a closed end. The length of the
side wall of each of said parts is generally greater than the
capsule diameter. The capsule caps and bodies may be telescopically
joined together so as to make their side walls partially overlap
and obtain a hard capsule shell.
As described herein, the term "partially overlap" is intended to
encompass the side walls of caps and bodies having the same or
similar length such that when a cap and a body are telescopically
joined, the side wall of said cap encases the entire side wall of
said body.
Unless otherwise indicated, "capsule" refers to filled capsule
shells whereas "shell" specifically refers to an empty capsule.
Since the hard capsule shells described herein can be filled with
substances in liquid form, the hard capsules may be sealed or
banded according to conventional techniques. Alternatively, the
hard capsule shells can be manufactured to have a specific capsule
shell design that provides certain advantages over conventional
techniques, e.g., the ability to pre-lock empty caps and bodies, or
completing the filling steps in a different location, or at a
specific time. Examples of such designs may be found it, for
example, WO 2009/138920 and WO 2009/050646.
The term "active ingredient" is used to indicate a component of the
compositions, capsule shells, and capsules described herein that is
pharmaceutically or physiologically active. Thus, it would be
understood that any compound that is pharmaceutically or
physiologically active, or that may take the benefit of delayed
release, is considered to be an active ingredient. For example,
acetaminophen, ibuprofen, or caffeine would be considered active
ingredients.
Unless otherwise indicated, "bulk enteric properties" means that
the capsule shells described herein are soluble in, or
disintegrated by alkaline intestinal secretions, but are
substantially insoluble or resistant in acid secretions of the
stomach. Disintegration and dissolution properties can be tested
according to <701>, USP34-NF29, page 276; <711>,
USP34-NF29, page 278; and <2040>, USP34-NF29, page 871.
In one embodiment, the present disclosure provides an aqueous
composition for the manufacture of enteric hard capsule shells,
said composition comprising:
(a) an aqueous dispersion of non-salified cellulose acetate
phthalate (CAP), said CAP being present in an amount ranging from
about 10% to about 40% by weight of the total weight of said
aqueous composition;
(b) at least one processing aid present in an amount ranging from
about 4% to about 20% by weight of the total weight of said aqueous
composition, wherein said at least one processing aid is selected
from polyoxyethylene-polyoxypropylene-polyoxyethylene tri-block
polymers or mixtures thereof, and comprise an average molecular
weight ranging from about 1000. to about 20000 and a
polyoxyethylene ratio ranging from about 10% to about 85%; and
(c) water.
In one embodiment, CAP is the only polymer displaying enteric
properties in the aqueous compositions. Thus, in one embodiment the
aqueous compositions do not contain polymers, except CAP, which
display enteric properties, e.g., polymers such as
polymethacrylates (copolymer of methacrylic acid and either methyl
methacrylate or ethyl acrylate--e.g. Eudragit.RTM. enteric family
members such as Eudragit.RTM. L); non CAP cellulose based polymers
e.g. CAT (cellulose acetate trimellitate); HPMCAS (hypromellose
acetate succinate); HPMCP (hydroxypropyl methylcellulose
phthalate); CMEC (Carboxy Methyl Ethyl Cellulose); or polyvinyl
derivatives e.g. polyvinyl acetate phthalate (Coateric.RTM. family
members).
An advantage of the aqueous compositions herein is that the CAP
amounts described allow for the manufacture of the hard capsule
shells, e.g. using a dip-moulding process, without the need to
incorporate other film-forming polymer(s) that are conventionally
used as base film-forming polymers for hard capsule shells. In
other words, non-salified CAP can be used along with the processing
aids in amounts that provide films endowed with sufficient film
forming properties such as thermal properties (DSC and MFT),
thermo-rheological properties and mechanical properties (e.g.
Young's module and brittleness). Accordingly, in one embodiment,
the aqueous compositions may comprise film-forming polymer(s)
conventionally used as base film-forming polymers for hard capsule
shells in amounts less than 5% by weight, e.g., less than 1% by
weight over the weight of the shell. Alternatively, in one
embodiment, the aqueous compositions do not contain film-forming
polymer(s) conventionally used as base film-forming polymers for
hard capsule shells.
In one embodiment, film-forming polymer(s) conventionally used as
base film-forming polymers for hard capsule shells include, for
example, cellulose non enteric derivatives. Examples include HPMC
(e.g. HPMC types 2910, 2906 and/or 2208 as defined in USP30-NF25),
gelatin, pullulan, PVA and non enteric starch derivatives, such as
hydroxypropyl starch.
In one embodiment, the processing aid comprises a
polyoxyethylene-polyoxypropylene-polyoxyethylene block
polymer--ingredient b) and B). This ingredient is also known in the
field of polymers with the following synonyms:
polyoxyethylene-propylene glycol copolymer,
polyoxyethylene-polyoxypropylene copolymer; commercial names of
families of polyoxyethylene-polyoxypropylene-polyoxyethylene block
polymers are: Lutrol.RTM., Monolan.RTM., Pluronic.RTM.,
Supronic.RTM., Synperonic.RTM.; CAS name
.alpha.-Hydro-.omega.-hydroxypoly(oxyethylene)poly(oxypropylene)poly(oxye-
thylene) block copolymer; CAS number 9003-11-6. Reference below is
made to ingredient b), only. However, these references must be
understood as being valid also for ingredient B), since both
ingredients comprise a
polyoxyethylene-polyoxypropylene-polyoxyethylene block polymer.
In one embodiment ingredient b) is selected from poloxamers and
mixtures thereof. Poloxamers are well-known non-ionic polymers.
Examples of poloxamers may be found in, e.g., U.S. Pat. No.
3,740,421.
The language poloxamer or poloxamers refers to
polyoxyethylene-polyoxypropylene-polyoxyethylene (POE-POP-POE)
triblock copolymers having the following Formula (I):
##STR00001## wherein a and b are integers and determined by the
initial amounts of POE and POP used in the polymerization process
as well as the polymerization process conditions. Within the
molecular weight range of between about 1000 to about 20000,
appropriate a/b ratios can be selected based on the desired
hydrophilic/hydrophobic properties of the final polymer (since the
POE blocks bring hydrophilicity whereas POP blocks bring
hydrophobicity).
In one embodiment, poloxamers suitable in the context of the
present disclosure, include those for which the
hydrophile-lipophile balance (HLB) of the hydrophilic and
lipophilic moieties is higher than 5, such as higher than 7, and
higher than 12.
In one embodiment, poloxamers are selected from those defined in
the USP32-NF27 "poloxamers" monograph. Examples of such products
are Poloxamer 124 and Poloxamer 188, having an average MW range of
2090 to 2360 and 7680 to 9510 respectively; and a polyethylene
oxide ratio of about 45% to about 80% respectively. Mixtures of
poloxamers, such as USP32-NF27 poloxamers, are also within the
scope of the invention.
In one embodiment, the
polyoxyethylene-polyoxypropylene-polyoxyethylene block polymer
comprises Poloxamer 124 (commercially available from BASF as
Lutrol.RTM. L44).
In one embodiment, the
polyoxyethylene-polyoxypropylene-polyoxyethylene block polymer
comprises or consists of Poloxamer 188 (commercially available from
BASF as Pluronic.RTM. F68NF).
In one embodiment, the
polyoxyethylene-polyoxypropylene-polyoxyethylene block polymer
comprises a mixture of poloxamers 124 and 188.
In one embodiment, the
polyoxyethylene-polyoxypropylene-polyoxyethylene block polymer is a
mixture comprising, Poloxamer 188 and Poloxamer 124 as defined
wherein the ratio between the amounts of Poloxamer 124 and
Poloxamer 188 ranges from 0 to about 0.9, such as from about 0.2 to
0.9, and from about 0.7 to about 0.9.
In one embodiment, the processing aid comprises, a
polyoxyethylene-polyoxypropylene-polyoxyethylene tri-block polymer
having an average molecular weight ranging from about 1000 to about
20000, said processing aid being present in an amount ranging from
about 4% to about 20% by weight over the total weight of aqueous
composition of the invention.
In one embodiment, the processing aid comprises, a mixture of
polyoxyethylene-polyoxypropylene-polyoxyethylene tri-block
polymers, each polymer in the mixture having an average molecular
weight between about 1000 to about 20000, said processing aid being
present in an amount between about 4% to about 20% by weight over
the total weight of aqueous composition.
In the aqueous compositions described herein, as well as the shells
described herein, a processing aid as defined above is present in
an amount ranging from about 4% to about 20% by weight, such as
from about 4% to about 15% by weight, and from about 5% to about
11% by weight over the total weight of aqueous compositions.
In one embodiment, the aqueous composition comprises a total amount
of solids, such as CAP and the at least one processing aid, ranging
from about 14.9% to about 50% combined, by weight of the total
weight of the composition. In other embodiments, the total amounts
of solids range from about 20% to about 50% and about 25% to about
40% by weight of the total weight of the composition.
In one embodiment, the total amount of CAP and the at least one
processing aid range from about 14.9% to about 50% combined, e.g.,
from about 20% to about 50% and about 25% to about 40%, by weight
of the total weight of the composition.
In one embodiment, the non-salified CAP is present in an amount
ranging from about 10% to about 40% by weight, e.g., from about 10%
to about 30% by weight, from about 15% to about 25% by weight, and
from about 15% to about 20% by weight of the total weight of the
aqueous composition.
In one embodiment, non-salified CAP is the only CAP present in the
aqueous compositions or the described capsule shells or capsules of
the present disclosure.
In one embodiment, processing aids are selected from poloxamers or
mixtures thereof.
In one embodiment, the aqueous compositions described herein may
comprise one or more (d) pharmaceutically acceptable agents, food
acceptable colouring agents, or mixtures thereof.
Said agents may be selected from azo-, quinophthalone-,
triphenylmethane-, xanthene- or indigoid dyes; iron oxides or
hydroxides; titanium dioxide; or natural dyes and mixtures thereof.
Further examples are patent blue V, acid brilliant green BS, red
2G, azorubine, ponceau 4R, amaranth, D+C red 33, D+C red 22, D+C
red 26, D+C red 28, D+C yellow 10, yellow 2 G, FD+C yellow 5, FD+C
yellow 6, FD+C red 3, FD+C red 40, FD+C blue 1, FD+C blue 2, FD+C
green 3, brilliant black BN, carbon black, iron oxide black, iron
oxide red, iron oxide yellow, titanium dioxide, riboflavin,
carotenes, anthocyanines, turmeric, cochineal extract,
chlorophyllin, canthaxanthin, caramel, betanin and Candurin.RTM.
pearlescent pigments. Candurin.RTM. is manufactured and marketed by
Merck KGaA, Darmstadt, Germany and consist of titanium dioxide
and/or iron oxide--approved food and pharmaceutical colorants in
many countries--and potassium aluminium silicate as color carrier.
The latter is a natural, also widely approved, silicate also known
under the name of `mica`.
In one embodiment, the pharmaceutically acceptable agents, food
acceptable colouring agents, or mixtures thereof are present in an
amount ranging from about 0 to about 5% by weight, e.g., from about
0 to about 2.5% by weight, and from about 0 to about 1.5% by weight
over the total weight of the aqueous composition of the
invention.
In one embodiment, the aqueous compositions described herein
further comprise at least one film forming aid (e).
In one embodiment, the term "film forming aid" comprises one or
more plasticizers conventionally used in the manufacture of capsule
shells, notably hard capsule shells, and/or one or more viscosity
enhancers, i.e. natural as well as synthetic substances
conventionally used to optimize viscosity of aqueous compositions
for the dip moulding manufacture of hard capsule shells. Film
forming aids that display plasticizing properties include:
phtalique esters (e.g. dimethyl-, diethyl-, dibutyl-, diisopropyl-
and dioctyl-phtalate); citric esters (e.g. triethyl-, tributyl-,
acetyltriethyl- and acetyltributyl-citrate); phosphoric esters
(e.g. triethyl-, tricresyl, triphenyl-phosphate); alkyl lactate;
glycerol and glycerol esters; oils and fatty acid esters; butyl
stearate; dibutyl sebacate; dibutyl tartrate; diisobutyl adipate,
tributyrin; propylene glycol; polyethyleneglycol (PEG),
polyoxyethylene (PEO); and mixtures thereof.
In one embodiment, film forming aids are selected from thickening
agents, structuring agents, surfactants, and plasticizers, e.g.,
hypromellose; alkyl cellulose and other cellulosic derivatives;
polyvinyl acetate derivatives (PVAP); polysaccharides; glyceryl
esters; glycol esters; sorbitan monoesters; sorbitan
polyoxyethylene esters; polyoxyethylene (POE) ethers; glycerol;
polyethylene glycols; polyols; fatty acid esters; glycerol
polyethylene, glycol ricinoleate; macrogolglycerides; SLS; triethyl
citrate (TEC); Triacetine; alkyl phthalate; and mixtures
thereof.
In one embodiment, film forming aids are selected from HPMC, HPC,
EC, MC, CMEC, HPMCAS, and HPMCP.
In one embodiment film forming aids that display compatibility with
CAP are selected from cellulosic derivatives (e.g. HPMC, HPC) and
mixtures thereof.
In one embodiment film forming aids that display viscosity
enhancing properties are selected from: guar gum, xanthan,
carrageenans, gellan gum, carboxymethyl cellulose (CMC), alkyl
celluloses, polysaccharides, and mixtures thereof.
In one embodiment, film forming aids that display both plasticizing
and viscosity enhancing properties are selected from: glyceryl
esters (e.g. glyceryl monooleate and monolinoleate, medium chain
triglycerides--i.e. C.sub.6-C.sub.12 fatty acid esters of
glycerol); glycol esters (e.g. propylene glycol dicaprylocaprate
and monolaurate); sorbitan monoesters (e.g. sorbitan monolaurate
and monooleate); sorbitan polyoxyethylene esters (e.g.
polyoxyethylene sorbitan monolaurate, monopalmitate, monostearate
and monooleate); polyoxyethylene (POE) ethers (e.g. polyethylene
glycol dodecyl ether); glycerol; polyethylene glycols (e.g. PEG
4000, PEG 6000); glycerol polyethylene glycol ricinoleate;
linoleoyl macrogolglycerides; and mixtures thereof.
In one embodiment, film forming aids are selected from: sorbitan
monoesters (e.g. sorbitan monolaurate and monooleate); sorbitan
polyoxyethylene esters (e.g. polyoxyethylene sorbitan monolaurate,
monopalmitate, monostearate and monooleate); polyoxyethylene (POE)
ethers (e.g. polyethylene glycol dodecyl ether); glycerol;
Polyvinyl acetate derivatives (PVAP), cellulosic derivative (e.g.
HPMC, HPC, EC, MC, CMEC, HPMCAS, HPMCP) and mixtures thereof.
In one embodiment, film forming aids are present in the aqueous
composition in an amount ranging from about 0 to about 15% by
weight, such as about 0 to about 10% by weight, about 0 to about 8%
by weight over the total weight of the aqueous composition of the
invention.
In one embodiment, the water (c) is purified in a manner that is
acceptable for pharmaceutical uses as defined under USP purified
water in USP32 and USP34-NF29. It will be understood that the
aqueous composition described herein allow for non-aqueous solvents
in trace amounts. Typical non-aqueous solvents are for example
ethanol, or other low MW alcohols conventionally used as solvents,
chlorinated solvents, ethers.
In one embodiment, the aqueous compositions comprise ingredients
a), b), c) and e) as defined above. In another embodiment, the
aqueous compositions comprise ingredients a), b), c), d) and e) as
defined above.
In one embodiment, the present disclosure also provides capsule
shells comprising the aqueous compositions described herein, for
example, as bulk enteric hard capsule shells.
In one embodiment, hard capsule shells are obtainable using the
aqueous compositions disclosed above and the processes as disclosed
below, e.g., dip moulding.
In one embodiment, the hard capsule shells as described comprise a
shell thickness (after drying to bring the water content of the
shell below 6% by weight over the weight of the shell) lower than
about 250 .mu.m, e.g., at about 150 .mu.m, and at about 70 .mu.m.
Thus, in one embodiment, the shell thickness may range from about
70 to about 150 .mu.m.
It should be noted that the aforementioned shell thickness values
are difficult, if not impossible, to be obtain with manufacturing
methods that are alternative to dip moulding. For example,
injection moulding techniques typically produce shell thicknesses
of about 300 to about 500 .mu.m.
In one embodiment, the shells may or may not be externally coated
with additional one or more polymer layers. Alternatively, the
shells are monolayer, i.e., no external additional polymer layers
are present. Thus, in one embodiment, no additional functional
polymer layers are present.
Unless otherwise indicated, functional polymer layers means layers
containing functional polymers that impart a particular mechanical
or chemical properties to the coated shell. Functional polymers are
enteric polymers conventionally used to coat pharmaceutical solid
dosage forms and/or colonic release polymers (i.e. polymers used to
achieve disintegration of the coated dosage form in the colon
region of a subject). An overview of these polymers as applied to
hard capsule coatings, can be found in, for example, WO
2000/018377. Capsule banding or sealing are not presently
considered as applying additional external layer(s), hence banded
or sealed capsule shells and capsule are well within the scope of
the present disclosure.
In one embodiment, the present disclosure provides bulk enteric
hard capsule shells comprising:
(A) non-salified cellulose acetate phthalate (CAP), said CAP being
present in an amount ranging from about 40% to about 70% by weight
of the total weight of said capsule shell;
(B) at least one processing aid present in an amount ranging from
about 15% to about 49% by weight of the total weight of said
capsule shell, wherein said at least one processing aid is selected
from polyoxyethylene-polyoxypropylene-polyoxyethylene tri-block
polymers or mixtures thereof, and comprise an average molecular
weight ranging from about 1000 to about 20000 and a polyoxyethylene
ratio ranging from about 10% to about 80%; and
(C) water.
In one embodiment, the non-salified CAP is present in an amount
ranging from about 45% to about 65% by weight or about 55% to about
65% by weight over the total weight of the shell.
In one embodiment, the processing aid is present in an amount
ranging between about 20% to about 40% by weight or between about
30% to about 40% by weight over the total weight of said CAP in
said composition and shell, respectively. The shell may comprise
any one of the processing aids or mixtures of processing aids as
discussed above in connection with the aqueous composition.
Typical amounts of water are below 20% by weight over the total
weight of the shell, such as below 10% by weight, below 8% by
weight, and below 6% by weight over the total weight of the
shell.
In one embodiment, the amount of water, as equilibrated with the
relative humidity of the outside air, ranges from about 2% to about
20% by weight of the total weight of the capsule shell.
In one embodiment, the hard capsule shells further comprise at
least one encapsulated active ingredient. Thus, the capsules may be
filled with one or more acid-instable substances and/or one or more
substances associated with gastric side effects in humans and/or
animals.
In one embodiment, acid-instable substances are natural or
synthetic substances that undergo chemical degradation or
modification in the acid environment present in the stomach of a
subject. In one embodiment, substances associated with gastric side
effects are pharmaceutical drugs or compositions intended for human
or animal oral administration, whose release in the stomach upon
oral administration to a human or animal being is associated to
gastric side-effects, such as gastric reflux or impairment of
physiological and/or structural integrity of gastric mucosa (e.g.
stomach ulcers).
In one embodiment, the at least one active ingredient comprises a
solid, semi-solid, or liquid form.
In one embodiment, the shells further comprise ingredient (D), one
or more pharmaceutically or food acceptable colouring agents, as
defined above. One or more pharmaceutically acceptable agents or
food acceptable colouring agents are present in amounts ranging
from 0 to about 15% by weight, such as, from 0 to about 10% by
weight and from 0 to about 8% by weight over the total weight of
the shells.
In one embodiment, the shells further comprise ingredient (E), film
forming aids as defined above. Film forming aids may be present in
amounts ranging from 0 to about 40% by weight, such as, from 0 to
about 30% by weight and from 0 to about 25% by weight over the
total weight of the shells.
In one embodiment, the shells may comprise ingredients A), B), C)
and E) as defined above. In another embodiment, the shells may
comprise ingredients A), B), C), D) and E) as defined above.
In one embodiment, the present disclosure also provides hard
capsule shells and processes for making the hard capsule shells
described herein, wherein the capsule shells comprise a
disintegration release of less than about 10% of the total
encapsulated at least one active ingredient after a time of about 2
hours and about pH 1.2.
In another embodiment, the present disclosure also provides hard
capsule shells and processes for making the hard capsule shells
described herein, wherein the capsule shells comprise a dissolution
release of less than about 10% of the total encapsulated at least
on active ingredient after at time of about 2 hours and about pH
1.2.
In one embodiment, the hard capsule shells comprise a
disintegration release of less than about 10% of the total
encapsulated at least one active ingredient after a time of about 2
hours and about pH 1.2 and a dissolution release of less than about
10% of the total encapsulated at least on active ingredient after
at time of about 2 hours and about pH 1.2.
In one embodiment, the dissolution release is about 80% of the
total encapsulated at least one active ingredient at a time of
about 45 minutes and about pH 6.8.
In one embodiment, capsule shells have bulk enteric properties when
they have dissolution and disintegration profiles that at least
match the disintegration and dissolution profiles reported above.
These disintegration and dissolution profiles in enteric media are
difficult if not impossible to be achieved by capsule shells
obtained using water based compositions containing lower amounts of
enteric polymer (including CAP). Because conventional use has been
to use the enteric polymer in solution and not the described
dispersion, the use of much lower amounts of enteric polymer was a
considered to be a mandatory feature, which does not apply
here.
The described filled capsules may be made tamper-proof by using
appropriate techniques to make the joint permanent. Typically,
sealing or banding techniques can be used where these techniques
are well-known to any skilled person in the field of capsules. In
this connection, it is conventional practice to perform banding
and/or sealing using polymer solutions in water/ethanol or
water/isopropanol solutions. Traces of such non water solvents can
be found if an elemental analysis is performed on a sealed or
banded capsule without making a distinction between ingredients
that are part of the shell and ingredients that are part of the
band or sealing subsequently applied.
Processes to make the aforementioned capsule shells and capsules
comprising the aqueous composition described herein are also
disclosed. Despite the high solid content, the aqueous compositions
described herein have low viscosity when the non-salified CAP is in
a dispersed state and not in solution. The low viscosity of the
aqueous solutions results in a dip moulding process that is easy
and advantageous.
In one embodiment, the viscosity of the aqueous compositions
described herein, when measured at 21.degree. C. with a Brookfield
viscosimeter equipped with a spindle 27 at a speed of 10 RPM, range
from about 1 cP to about 5000 cP, e.g., from about 500 cP to about
3000 cP, and from about 1000 cP to about 2500 cP.
In one embodiment, the aqueous compositions to be used in the
context of the dip-moulding processes described below are the
aqueous compositions as discussed above. Accordingly, any
consideration and embodiment discussed in connection with the
aqueous compositions apply to the dip-moulding processes described
herein to the extent that it is technically possible.
Accordingly, in one embodiment, the present disclosure provides
dip-moulding processes for the manufacture of bulk enteric hard
capsule shells, wherein the processes comprise:
i) providing an aqueous composition comprising (a) an aqueous
dispersion of non-salified cellulose acetate phthalate (CAP), said
CAP being present in an amount ranging from about 10% to about 40%
by weight of the total weight of said aqueous composition; (b) at
least one processing aid present in an amount ranging from about 4%
to about 20% by weight of the total weight of said aqueous
composition,
wherein said at least one processing aid is selected from
polyoxyethylene-polyoxypropylene-polyoxyethylene tri-block polymers
or mixtures thereof, and comprise an average molecular weight
ranging from about 1000 to about 20000 and a polyoxyethylene ratio
ranging from about 10% to about 85%; and (c) water;
ii) adjusting said aqueous composition to a temperature (T1)
ranging from about 5.degree. C. to about 40.degree. C.;
iii) pre-heating moulding pins at a dipping temperature (T2)
ranging from about 15.degree. C. to about 70.degree. C. higher than
said temperature T1;
iv) dipping the pre-heated moulding pins into said aqueous
composition;
v) forming a film on said moulding pins by withdrawing said pins
from said aqueous composition; and
vi) drying the film on said moulding pins to form bulk enteric hard
capsule shells.
In one embodiment, the aqueous composition is kept in step ii) at a
temperature ranging from about 5.degree. C. to about 40.degree. C.,
such as, for example from about 15.degree. C. to about 35.degree.
C. and about 15.degree. C. to about 25.degree. C.
In one embodiment, pins are pre-heated and dipped at a temperature
ranging from about 15.degree. C. to about 70.degree. C. higher than
the temperature of the aqueous composition in step ii). For
example, the temperature may range from about 15.degree. C. to
about 50.degree. C. and from about 25.degree. C. to about
50.degree. C. higher than the temperature of the aqueous
composition in step ii). In one embodiment, pins are pre-heated to
a temperature ranging from about 45.degree. C. to about 90.degree.
C.
In one embodiment, step iv) comprises a single dipping of the pins.
In other words, no multiple dipping of the pins is necessary to
obtain a pick-up of material on pins surface sufficient to obtain a
film endowed with required mechanical properties.
In one embodiment, step vi) of drying is performed according to
drying techniques typically applied in the field of hard capsules,
which can be accomplished using equipment known to the skilled
person for this purpose. In one embodiment, step vi) of drying can
be performed according to any technique commonly known for this
purpose, for example by placing the pins in ovens. In one
embodiment, step vi) of drying is performed at a temperature
ranging from about 20.degree. C. to about 90.degree. C.
In one embodiment, the moulding processes further comprise a step
vii) of filling hard capsules shells with one or more substances as
disclosed above.
In one embodiment, the moulding processes further comprise a step
viii) of making a filled hard capsule tamper-proof by sealing
and/or banding the filled hard capsule obtained in step vii).
Without wanting to be bound by any theory, it is believed that the
temperature T2 is high enough to induce coalescence in the aqueous
composition. The temperature at which the aqueous composition
coalesces can also be referred to as setting temperature, above the
minimum film-forming temperature (MFFT). Setting temperature is a
parameter of aqueous compositions to be used in the manufacture of
hard capsules that is well known to any skilled person. The
difference with conventional methods (e.g. thermogelling
dip-moulding processes known for the manufacture of hard capsule
shells using cellulose derivatives like HPMC) is that the setting
temperature identifies the gelification of the composition whereas
in the present disclosure it identifies the coalescence of the
composition.
EXAMPLES
A suitable test procedure to test disintegration properties of the
shells (and capsules) is as follows:
USP Apparatus basket-rack assembly consisting of six open-ended
transparent tubes, each tube being provided with a disk;
Disintegration media: simulated gastric fluid at pH 1.2 with NaCl
for 2 h then simulated intestinal fluid at pH 6.8 with
KH.sub.2PO.sub.4+NaOH; Test conditions: fluid kept at 37.degree.
C.; oscillation frequency was 30/min; volume of dissolution medium
was 800 ml; number of samples tested was 6. Test shells #0 are
pre-filled with 450 mg of a mix of lactose plus 0.1% B2 (indigo
blue). Capsules are placed in the tubes and a disk is over imposed.
The basket is then placed in the simulated gastric fluid for 2 h
and then moved to the simulated intestinal fluid.
A suitable test procedure for dissolution properties of the shells
(and capsules) is as follows:
USP Dissolution Apparatus 2 (paddle), dissolution media: simulated
gastric fluid at pH 1.2 0.1N HCl for 2 h then simulated intestinal
fluid at pH 6.8 with Na.sub.3PO.sub.4; Test conditions: fluid kept
at 37.degree. C., paddle vessel (USP/NF) of cylindrical form with
spherical end; rotation speed was 50 rpm; dissolution liquid volume
is 750 ml; number of samples is 6. Test shells #0 are filled with
380 mg of acetaminophen. Capsules are then placed into the vessel
which is placed in the simulated gastric fluid for 2 h.
Subsequently, 250 ml of 0.20M tribasic sodium phosphate are added
to simulated intestinal fluid pH 6.8. UV (.lamda.=300 nm) is used
to quantify dissolved acetaminophen (as % of filled amount) in the
dissolution media. Measures are made every 15 minutes when in the
simulated gastric fluid and every 3 minutes in the simulated
intestinal fluid.
When tested according to USP32-NF27 monographs <701> and
<711> for delayed-release dosage forms, respectively, the
capsule shells once filled with acetaminophen showed at least the
following profiles: Disintegration: release less than 10% of total
encapsulated acetaminophen after 2 hours at pH 1.2; and
Dissolution: release less than 10% of total encapsulated
acetaminophen after 2 hours at pH 1.2, where 80% of the
acetaminophen was released after 45 minutes at pH 6.8. Description
of the Test Protocols
a) Determination of the Ability for the Aqueous Dispersion to Form
a Continuous Film
The prepared aqueous dispersion is casted on a hot (60.degree. C.)
glass plate using Capsugel film cast equipment (modified motorized
Thin Layer Chromatography Plate Coater unit from CAMAG) or any
other conventional drawdown coating equipment to make a uniform
thin film having a dry thickness of about 100 .mu.m. The casted
film on the glass plate is kept in an oven during 1 hour at
60.degree. C., and then stored for at least 2 hours at room
temperature and 50% RH to allow full drying. Once dried, the
obtained film is removed from the glass plate and evaluated for
visual, physical properties, and thermal properties (including DSC
and minimum film-forming temperature (MFFT) as per standard
operating procedures for films and coating evaluation).
b) Evaluation of the Aqueous Dispersion Setting Properties
To reproduce the capsule dipping process, a simplified lab-scale
equipment called Pin Lab Dipper has been developed to mimic the
dipping of a pin into the solution. This device is equipped with an
electronically-assisted module to control the pin dipping profile
and withdrawal profile. It also ensures the pin rotation to the
upright position and regulates the pin temperature. The dipping
step is followed by a drying sequence with appropriate hot air.
This test evaluates the potential setting properties of the tested
solutions, whether it is possible to form a continuous and
homogeneous film on the stainless steel pin by dip moulding
processes.
Setting conditions for Example 1 below: dipping dish container at
21.degree. C., pre-heated pin at 70.degree. C., drying temperature
60.degree. C. at room relative humidity. Visual control of capsule
shell for possible defect, weight and thickness measurement (top
wall, side wall and/or shoulder).
Example 1
Preparation of the Aqueous Dispersion
In a reactor of 300 mL, 60 g of Poloxamer (Lutrol L44 from BASF)
are mixed with 140 mL of purified water under gentle stirring for
30 min. The obtained solution is poured in a 2-liter reactor
containing 1000 g of Aquacoat CPD 30 dispersion from FMC at room
temperature and stirred overnight for 12 hours for complete
homogenization at 21.degree. C. Usually, the viscosity of the
formulation increases slightly from milk to liquid cream during
this maturation step. A film and a capsule shell are prepared from
this dispersion and evaluated according to the protocols described
above under a) & b).
Example 2
Evaluation of Reduced Quantity of Poloxamer
In a reactor of 200 mL, 45 g of Poloxamer 124 (Lutrol L44) are
mixed with 105 mL of purified water under gentle stirring for 30
min. The obtained solution is poured in a 2-liter reactor
containing 1000 g of Aquacoat CPD 30 dispersion at room temperature
and stirred overnight for 12 hours for complete homogenization at
21.degree. C. (Example 2). A film and a capsule shell are prepared
from this dispersion and evaluated according to the protocols
described above under a) & b).
Example 3
In a reactor of 150 mL, 30 g of Poloxamer 124 (Lutrol L44) are
mixed with 70 mL of purified water under gentle stirring for 30
min. The obtained solution is poured in a 2-liter reactor
containing 1000 g of Aquacoat CPD 30 dispersion at room temperature
and stirred overnight for 12 hours for complete homogenization at
21.degree. C. (Example 3). A film and a capsule shell are prepared
from this dispersion and evaluated according to the protocols
described above under a) & b).
Results:
TABLE-US-00001 poloxamer/ Young Elongation Example Commercial CAP
viscosity modulus at break MFFT Tg # name ratio film (cP) (3) MPa
(2) % (2) (.degree. C.) (.degree. C.) capsule shell (1) 1 Lutrol
L44 1/5 uniform film 1300 720 40 30 47 adequate pick-up 2 Lutrol
L44 3/20 uniform film 800 860 30 30 46 satisfying pick-up 3 Lutrol
L44 1/10 cracked film 21 N/A N/A 30 45 no pick up (1) pick up:
formation of a continuous & homogeneous film of about 100 .mu.m
+/- 20 .mu.m on the stainless steel pin (2) film stored at 23% RH,
measured with Instron 4443, 4 .times. 0.5 inches tensile specimens
(3) measured with Brookfield, spindle 27, 10 RPM, 21.degree. C.
Examples 4-10
The aqueous dispersions of Examples 4, 5, 6, 7, 8, 9 and 10 have
been prepared to compare various grades of poloxamer (Pluronic from
BASF) according to the protocol described for Example 1, with
respectively Pluronic F108, Pluronic F127, Pluronic F68, Pluronic
F87, Pluronic L35, Pluronic L43, Pluronic L62 instead of Lutrol L44
in the same proportions: 1/5 (w/w) poloxamer (30% solution)/CAP
(30% dispersion) ratio. A film and a capsule shell are prepared
from this dispersion and evaluated according to the protocols
described above under a) & b).
Results:
TABLE-US-00002 Example Commercial Poloxamer # name grade (2) Mw (2)
EO % (2) HLB (2) Observation 4 Pluronic F108 338 16500 80 >24 no
pick up (1) 5 Pluronic F127 407 13333 70 >24 no pick up (1) 6
Pluronic F68 188 9000 80 >24 no pick up (1) 7 Pluronic F87 237
7666 70 >24 no pick up (1) 8 Pluronic L35 N/A 1900 50 18-23 weak
thin film formed 1 Lutrol L44 124 2000-2200 40 12-18 adequate film
formed 9 Piuronic L43 N/A 1850 30 7-12 weak thick film formed 10
Pluronic L62 182 2450 20 1-7 poor thick film formed (1) pick up:
formation of a continuous & homogeneous layer/film on the
stainless steel pin (2) data according to BASF technical
datasheets
Example 11
Evaluation of a Blend with Hypromellose (HPMC) as Film-Forming
Aid
In a reactor of 300 mL, 60 g of Poloxamer 124 (Lutrol L44) are
mixed with 140 ml of purified water under gentle stirring for 30
min. The obtained solution is poured in a 2-liter reactor
containing 1000 g of Aquacoat CPD 30 dispersion and 600 g of a HPMC
20% solution at room temperature and stirred overnight for 12 hours
for complete homogenization at 21.degree. C. A film and a capsule
shell are prepared from this dispersion and evaluated according to
the protocols described above under a) & b).
Example 12
Evaluation of the Opacification
In a reactor of 300 mL, 60 g of Poloxamer 124 (Lutrol L44) are
mixed with 140 mL of purified water under gentle stirring for 30
min. The obtained solution is poured in a 2-liter reactor
containing 1000 g of Aquacoat CPD 30 dispersion at room temperature
and stirred overnight for 12 hours for complete homogenization at
21.degree. C. After maturation, a titanium dioxide slurry is added
to the obtained dispersion under gentle stirring until complete
homogenization at 21.degree. C., at a ratio of 5/95 (w/w
slurry/dispersion). The titanium dioxide slurry comprises 21.8% of
TiO.sub.2, 19.4% of a 20% HPMC solution, 58.1% of water pH 4 and
0.7% of a cationic compound such as chitosan. The chitosan is first
pre-dispersed in the water pH 4 and the solution is defoamed
overnight. TiO.sub.2 is then added and dispersed 3.times.2 min at
Vmax with a high speed homogenizer such as Ultra-Turrax. Then the
HPMC solution is added and stirred 3 min at 1200 RPM with a high
speed homogenizer. In addition, 0.2% of pigment Patented Blue
dispersed in a minimum of water is optionally incorporated to the
final preparation under gentle stirring to obtain an opaque blue
film and capsule shell. A film and a capsule shell are prepared
from this dispersion and evaluated according to the protocols
described above under a) & b).
Example 13
Thickening agent: In a reactor of 200 mL, 45 g of Poloxamer 124
(Lutrol L44 from BASF) are mixed with 105 ml of purified water
under gentle stirring for 30 min. In a separate beaker of 100 mL, 3
g of carboxymethyl cellulose (Blanose 7MF-PH from Ashland) are
added to 72 mL of purified water under high speed homogenization,
using for example an Ultra-Turrax homogenizer during 20 min before
a 30 min-defoaming step under vacuum. Both obtained Poloxamer and
Blanose solutions are poured in a 2-liter reactor containing 1000 g
of Aquacoat CPD 30 dispersion at room temperature and stirred
overnight for 12 hours for complete homogenization at 21.degree. C.
A film and a capsule shell are prepared from this dispersion and
evaluated according to the protocols described above under a) &
b).
Example 14
In a reactor of 300 mL, 60 g of polyoxyethylene (Polyox N10 from
Dow) are mixed with 140 mL of purified water under gentle stirring
(150 RPM) at 80.degree. C. during one night. The obtained solution
is then cooled down at room temperature and poured in a 2-liter
reactor containing 1000 g of Aquacoat CPD 30 dispersion comprising
23% of non-salified CAP and about 7% of Poloxamer; the mixture is
stirred during one night at 200 RPM for complete homogenization at
21.degree. C. A film and a capsule shell are prepared from this
dispersion and evaluated according to the protocols described above
under a) & b).
Example 15
Gelling agent: In a reactor of 300 mL, 1.4 g of carrageenan
(Satiagum UTC 10 grade lambda from Cargill) is mixed with 140 mL of
purified water under gentle stirring for 30 min. Then 60 g of
Poloxamer 124 (Lutrol L44) is added to this solution under gentle
stirring for 30 min. The obtained solution is poured in a 2-liter
reactor containing 1000 g of Aquacoat CPD 30 dispersion at room
temperature and stirred overnight for 12 hours for complete
homogenization at 21.degree. C. A film and a capsule shell are
prepared from this dispersion and evaluated according to the
protocols described above under a) & b).
Results:
TABLE-US-00003 Example viscosity Young modulus Elongation at # film
(cP) (3) (MPa) (2) break % (2) capsule shell (1) 11 uniform film
>2000 867 29 adequate pick-up 12 uniform thick film N/A 515 45
adequate opaque pick-up (optionnally blue) 13 uniform slightly
bitty film 1762 740 41 satisfying pick-up 14 thick film N/A 669 12
adequate pick-up 15 uniform transparent film 1987 614 48 adequate
pick-up (1) pick up: formation of a continuous & homogeneous
film on the stainless steel pin (2) film stored at 23% RH, measured
with Instron 4443, 4 .times. 0.5 inches tensile specimens (3)
measured with Brookfield, spindle 27, 10 RPM, 21.degree. C.
Examples 16-18
Evaluation of various process conditions on PLD--Dispersion
temperature: An aqueous dispersion of CAP and Poloxamer is prepared
according to the Example 1. It is then poured into the dipping dish
container of the electronically-assisted Pin Lab Dipper, in which a
robotized hot pin at 70.degree. C. is dipped and withdrawn
according to a pre-established sequence before drying at 60.degree.
C. The dipping dish container temperature is respectively set at
14.degree. C., 18.degree. C. and 24.degree. C. for Examples 16, 17
and 18.
Examples 19 and 20
Evaluation of various process conditions on PLD--Pin temperature:
An aqueous dispersion of CAP and Poloxamer is prepared according to
the example 1. It is then poured into the dipping dish container at
21.degree. C. of the electronically-assisted Pin Lab Dipper, in
which a robotized hot pin is dipped and withdrawn according to a
pre-established sequence before drying at 60.degree. C. The pin
temperature is respectively set at 67.degree. C. and 73.degree. C.
for the example 19 and 20.
Results:
TABLE-US-00004 Example dish T pin T body * side wall * top wall *
shoulder * viscosity # .degree. C. .degree. C. weight (g) thickness
(.mu.m) thickness (.mu.m) thickness (.mu.m) (cP) (1) Observation 1
21 70 60 100 125 80 1350 adequate pick-up 16 14 70 <40 <60
broken broken <800 no pick up 17 18 70 44 80 90 50 1150 thin
film 18 24 70 68 120 150 85 1550 thick film 19 21 67 50 95 85 60
1350 thin film 20 21 73 60 110 125 80 1350 slightly thick film *
average data (1) measured with Brookfield, spindle 27, 10 RPM,
21.degree. C.
Example 21
Evaluation of the aqueous dispersions on pilot capsule machine: In
a reactor of 1 L, 240 g of Poloxamer (Lutrol L44 from BASF) are
mixed with 560 ml of purified water under gentle stirring for 30
min. The obtained solution is poured in a 5-liter reactor
containing 4000 g of Aquacoat CPD 30 dispersion at room temperature
and stirred overnight for 12 hours for complete homogenization at
21.degree. C. Usually, the viscosity of the formulation increases
slightly from milk to liquid cream during this maturation step.
Manufacture of the capsules with pilot machine: The defined aqueous
dispersion is transferred into the dipping dish of a pilot machine
of conventional hard capsule production equipment. While keeping
the dipping solution at 21.degree. C., hot stainless steel pins
size 0 at 70.degree. C. (pins body or cap are pre-heated at
70.degree. C. in the corresponding section of the pilot machine)
are dipped into the aqueous dispersion according to a well defined
dipping profile in an attempt to manufacture capsules (body or cap)
with the same dimension specifications to the conventional hard
capsules. After withdrawal the dipped pins are transferred to a
drying section where they are submitted to hot air at defined
speed, temperature and humidity. When dry, the body or cap capsules
parts obtained are stripped of the pins, cut and assembled for
visual control and physical property measurements, including
weight, dimensional evaluation, and dissolution/disintegration
tests.
Examples 22 and 23
The aqueous dispersion is prepared according to the Example 21. It
is then transferred into the dipping dish of a pilot machine of
conventional hard capsule production equipment, to manufacture
capsules following the same protocol as described for Example 21.
The hot stainless steel pins are heated at 70.degree. C. The
dipping solution and the dipping dish container are kept at
19.degree. C. and 23.degree. C. for the respective Example 22 and
23.
Examples 24 and 25
The aqueous dispersion is prepared according to the Example 21. It
is then transferred into the dipping dish of a pilot machine of
conventional hard capsule production equipment, to manufacture
capsules following the same protocol as described for example 21.
The dipping solution and the dipping dish container are kept at
21.degree. C. The hot stainless steel pins are respectively heated
at 60.degree. C. and 65.degree. C. for the Examples 24 and 25.
Example 26
In a reactor of 1 L, 240 g of Poloxamer 124 (Lutrol L44) are mixed
with 560 ml of purified water under gentle stirring for 30 min. The
obtained solution is poured in a 5-liter reactor containing 4000 g
of Aquacoat CPD 30 dispersion at room temperature and stirred
overnight for 12 hours for complete homogenization at 21.degree. C.
After maturation, a titanium dioxide slurry is added to the
obtained dispersion under gentle stirring until complete
homogenization at 21.degree. C., at a ratio of 5/95 (w/w
slurry/dispersion). The titanium dioxide slurry comprises 21.8% of
TiO.sub.2, 19.4% of a 20% HPMC solution, 58.1% of water pH 4 and
0.7% of a cationic compound such as chitosan. The chitosan is first
pre-dispersed in the water pH 4 and the solution is defoamed
overnight. TiO.sub.2 is then added and dispersed 3.times.2 min at
Vmax with a high speed homogenizer such as Ultra-Turrax. Then the
HPMC solution is added and stirred 3 min at 1200 RPM with a high
speed homogenizer.
In addition, 0.25% of pigment yellow 6 dispersed in a minimum of
water is optionally incorporated to the final preparation under
gentle stirring at 21.degree. C. to obtain an opaque orange capsule
shell.
The defined aqueous dispersion is transferred into the dipping dish
of a pilot machine of conventional hard capsule production
equipment. While keeping the dipping solution at 21.degree. C., hot
stainless steel pins size 0 at 70.degree. C. (pins body or cap are
pre-heated at 70.degree. C. in the corresponding section of the
pilot machine) are dipped into the aqueous dispersion according to
a well defined dipping profile in an attempt to manufacture
capsules (body or cap) with the same dimension specifications to
the conventional hard capsules. After withdrawal the dipped pins
are transferred to a drying section where they are submitted to hot
air at defined speed, temperature and humidity. When dry, the body
or cap capsules parts obtained are stripped of the pins, cut and
assembled for visual control and physical property measurements,
including weight, dimensional evaluation, and
dissolution/disintegration tests.
Example 27
In a reactor of 1 L, 240 g of Poloxamer 124 (Lutrol L44) are mixed
with 560 mL of purified water under gentle stirring for 30 min. The
obtained solution is poured in a 5-liter reactor containing 4000 g
of Aquacoat CPD 30 dispersion and 2400 g of a HPMC 20% solution at
room temperature and stirred overnight for 12 hours for complete
homogenization at 21.degree. C.
The defined aqueous dispersion is transferred into the dipping dish
of a pilot machine of conventional hard capsule production
equipment. While keeping the dipping solution at 21.degree. C., hot
stainless steel pins size 0 at 70.degree. C. (pins body or cap are
pre-heated at 70.degree. C. in the corresponding section of the
pilot machine) are dipped into the aqueous dispersion according to
a well defined dipping profile in an attempt to manufacture
capsules (body or cap) with the same dimension specifications to
the conventional hard capsules. After withdrawal the dipped pins
are transferred to a drying section where they are submitted to hot
air at defined speed, temperature and humidity. When dry, the body
or cap capsules parts obtained are stripped of the pins, cut and
assembled for visual control and physical property measurements,
including weight, dimensional evaluation, and
dissolution/disintegration tests.
Results:
TABLE-US-00005 Example dish T pin T body * side wall * top wall *
shoulder * viscosity Observation # .degree. C. .degree. C. weight
(g) thickness (.mu.m) thickness (.mu.m) thickness (.mu.m) (cP)
defects 21 21 70 62 107 124 88-144 127 (1) adequate capsule 22 19
70 56 N/A 183 N/A 137 (1) many visual defects 23 23 70 67 N/A 198
N/A 194 (1) many visual defects 24 21 60 53 N/A 95 N/A 213 (2) thin
capsule 25 21 65 58 N/A 152 N/A 182 (2) adequate capsule 26 21 70
63 110 190 89 180 (1) adequate white capsule (optionally orange) 27
21 70 60 109 117 85 530 (1) adequate harder capsule * average data
for selected defined dipping profile Viscosity measured with
Capsugel pilot machine viscosimeter; speed (1) v = 3 (2) v = 5
Dissolution profile of a capsule shell containing acetaminophen.
UV-titration (300 nm)
TABLE-US-00006 time (min) 0 15 30 45 60 75 90 105 120 123 Example
21 % dissolved 0.00 0.10 0.30 0.55 0.80 1.02 1.25 1.45 1.62 2.88
Example 26 % dissolved 0.00 0.07 0.35 0.66 0.98 1.32 1.62 1.90 2.16
3.79 time (min) 126 129 132 135 140 145 150 155 170 185 Example 21
% dissolved 8.44 20.23 34.58 47.75 65.30 77.54 85.55 97.74 99.36
100.00 Example 26 % dissolved 6.10 14.97 32.97 50.90 71.71 84.28
91.17 99.04 98.98 99.11
As discussed above, existing process to obtain enteric (not
necessarily bulk enteric) capsules, e.g., double dipping techniques
or post-manufacturing techniques, require the use of multiple
steps, which is contrary to the present disclosure. Without wanting
to be bound by any theory, it is believed that the dip-moulding
processes described herein entail coalescence of the aqueous
composition on the surface of a conventional pin, assisted by a
thermo-gelling phenomenon due to the use of the processing aid b)
that is able to form thermo-reversible gels at elevated
temperature. In coalescence, it is considered that evaporation of
water occurs while boundaries between CAP dispersed particles
disappear, then the particles close-pack and lead to an uniform
phase domain; as per continuing evaporation and particle
compaction, polymer film starts forming with compacted (deformed)
CAP particles, leading to inter-particles diffusion of CAP polymer
molecules that generate isotropic polymer film. Thus, the present
disclosure provides coalescing dip-moulding techniques on the
aqueous CAP dispersion described above, wherein hard capsule shells
can be obtained that display bulk enteric properties without the
need to repeatedly (e.g. double) dip the pins or apply further
external enteric coatings to the already manufactured shells. By
juxtaposition to the presently disclosed "one step" processes,
earlier processes require at least a "second" step which may be the
second pin dipping step or the application step of a capsule
coating.
Furthermore, the present disclosure also accomplishes, in part, 1)
the use of aqueous compositions comprising an aqueous dispersion of
non-salified CAP; 2) the use of aqueous compositions as opposed to
non-aqueous (or solvent-based) CAP solutions, together with
processing aid (b); 3) the production of films on the moulding pins
surface by inducing coalescence of CAP dispersed particles in
contrast to polymer gelification; 4) the production of films on the
moulding pins surface without the need for other conventional based
film-forming polymer(s); 5) the ability to use of higher amounts of
CAP polymer; and 6) increased viscosity of the aqueous compositions
described herein that is otherwise unattainable by different
processes outside the scope of the present disclosure.
* * * * *